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Biomedical subjects

P Carmichael

Publications and source records attributed to P Carmichael.

17 recordsLinked to original sources
PubMed2001

Non-specialist management of acute renal failure.

In a 12-month prospective study of the initial management of patients with acute renal failure (ARF) in East Kent (population 593 000), we evaluated the initial management of ARF and assessed what proportion of ARF may have been preventable. Patients were seen and assessed on a daily basis, and were followed until discharge from hospital or death; survivors were subsequently followed for 3 years. Overall, 288 patients developed ARF (486 per million population/year). Mean age at presentation was 73 years (range 14-96). Initial assessment was often suboptimal, and key features in investigation and initial management were often lacking. In 108 cases, ARF was iatrogenic and/or potentially preventable (53 preventable, 99 iatrogenic, 44 both). Overall survival was 56% at discharge from hospital, 35% at 1-year follow-up, 31% at 2 years, and 28% at 3 years. In discharged patients, recovery of function was complete in 69%. A significant proportion of ARF is preventable. Clear guidelines, easily accessible at the point of care, could aid the diagnostic evaluation of the patient with ARF and indicate where referral for a specialist opinion is appropriate.

Acute Kidney Injury↗
PubMed2000

Assessment of quality of life in a single centre dialysis population using the KDQOL-SF questionnaire.

Health-related quality of life (HRQOL) is a valid marker of outcome for chronic dialysis therapy. A wide range of questionnaires are now available which assess different aspects of an individual's health. Appreciation of those factors that contribute to explaining HRQOL items remains poorly defined. The development of disease-specific questionnaires such as KDQOL-SF, should allow for such questions to be better answered. A cross-sectional analysis of our chronic dialysis population was made using the KDQOL-SF questionnaire. By multiple linear regression analysis demographic, clinical and dialysis-related factors were assessed for their contribution to the HRQOL in this population. The HRQOL of these patients was also compared against a general population sample. From a total of 190 chronic dialysis patients, 146 completed the KDQOL-SF questionnaire. The haemodialysis (HD) and peritoneal dialysis (PD) patients were similar with respect to most demographic, clinical and dialysis variables except for haemoglobin and albumin which were significantly (p < 0.05) greater in the peritoneal and haemodialysis populations respectively. Compared to the general population, the HRQOL of dialysis patients was impaired for all SF-36 subscales. Use of the disease-specific components of KDQOL-SF discriminated between dialysis modality for our dialysis population. Multiple linear regression analysis demonstrated that 27.5 to 42.7% of the variance in the SF-36 subscales could be explained. Satisfactory sleep, dialysis related symptoms, effect of kidney disease on lifestyle and burden of kidney disease were found to be the most important determinants of HRQOL for this population.

Aged↗
PubMed1999

Biased T-cell receptor usage is associated with allelic variation in the MHC class II peptide binding groove.

A comprehensive analysis was carried out of the tri-molecular complex of peptide, major histocompatibility class II molecule, and T-cell receptor (TcR) involved in the recognition of the promiscuous HA (306-318) peptide, restricted by one of two closely related HLA-DR alleles, HLA-DRB1*0101 and HLA-DRB1*0103. These two DR molecules differ by only three amino acids at positions 67, 70, and 71, in the third variable region of the DRB1 chain. None of the HA (306-318)-specific T-cell clones restricted by these two DR molecules tolerated amino acid substitution at the peptide-binding position 71, despite the fact that the substitution did not interfere with peptide binding. The majority of the DRB1*0103-restricted clones tolerated substitution of the amino acid at the TcR-contacting position 70, while the DRB1*0101-restricted T cells did not. Based usage of TRVA and TRVB segments was observed for the DRB1*0103-restricted clones; in contrast, apparently random usage was seen in the DRB1*0101-restricted T cells. Finally, limiting dilution analysis revealed a lower frequency of T cells reactive with the HA peptide in a DRB1*0103 compared with a DRB1*0101 individual. Taken together these data suggest that biased TcR gene usage may reflect a relatively low precursor frequency of T cells, and the need for clonal expansion of a limited set of high avidity T cells.

Alleles↗
PubMed1999

Atherosclerotic renal artery stenosis: from diagnosis to treatment.

Renovascular hypertension represents a form of correctable hypertension and preventable renal failure. Such patients need to be identified early so that specific therapy can be instigated. Patient identification requires a high index of suspicion in patients with certain clinical features. Subsequent non-invasive imaging may result in angiography which is required for diagnostic purposes and for planning intervention. Correctable therapy takes one of two forms, namely percutaneous transluminal renal angioplasty, with or without stenting, or surgical revascularisation, together with modification of underlying risk factors.

Aged↗
PubMed1998

Interferon-gamma-treated renal tubular epithelial cells induce allospecific tolerance.

Following organ transplantation, tissue parenchymal cells commonly express major histocompatibility complex (MHC) class II molecules as a result of local cytokine release, and thus acquire the capacity to present donor MHC alloantigens to alloreactive CD4+ T cells. The consequences of such a presentation are likely to be relevant in the induction of tolerance to the transplanted tissues, and this has been reported in animal models of transplantation and in humans. In this study, the consequences of antigen presentation by interferon-gamma (IFN-gamma)-treated human renal tubular epithelial cells (RTEC) to resting and activated CD4+ T cells were investigated. Allogeneic RTEC were unable to stimulate proliferation by peripheral blood CD45 RA+ or RO+ CD4+ T cells from three HLA-mismatched responders. The response to RTEC was partially reconstituted by the addition of murine L cell transfectants expressing human B7.1 (DAP.3-B7), suggesting that the failure of RTEC to stimulate a primary alloresponse was due, at least in part, to a lack of costimulation. T cell clones dependent on B7-mediated co-stimulation also did not respond to peptide presented by RTEC. Most importantly, this lack of reactivity was accompanied by the induction of nonresponsiveness. Incubation with allogeneic, DR-expressing RTEC induced allospecific hyporesponsiveness in both CD45RA+ and RO+ cells. Similarly, overnight incubation with antigen-pulsed RTEC induced nonresponsiveness in the B7-dependent T cell clones. These results suggest that MHC class II expression on RTEC may contribute to the induction of an allospecific nonresponsiveness following organ transplantation.

Animals↗
PubMed1997

Allele-specific variation in the degeneracy of major histocompatibility complex (MHC) restriction.

The role of peptides in determining immune responses for both allorecognition and antigen-specific recognition has been clearly documented. The importance of different regions of the major histocompatibility complex (MHC) class II molecule in contributing to recognition has been demonstrated by studies involving site-directed mutagenesis and exon shuffling. These studies have indicated that the N-terminal region of the MHC class II molecule has a role to play in contributing to the T-cell receptor (TCR)-MHC-peptide interaction. Variation in the importance of different regions of the MHC class II molecule may be dependent on different aspects of this interaction, such as restriction specificity and affinity of the responding T-cell clone, and the nature of the bound peptide. We demonstrate here that the degree of T-cell degeneracy may be allele dependent. Thus, a series of exon-shuffled molecules were generated by shuffling the first and second variable region of a particular DR beta 1 molecule with the third variable region of a different DR beta 1 molecule. A panel of transfectants, which expressed these hybrid molecules, was then generated and used as antigen-presenting cells (APCs). A panel of peptide-specific T-cell clones was generated using the native HLA-DR molecules as the restricting elements. For the majority of restricting alleles, HLA-DRB5*0101, HLA-DRB1*1101, and HLA-DRB1*0701, all three variable regions were required for recognition. The exception to this observation was HLA-DRB1*0401, which was degenerate. Such degeneracy may facilitate the breakdown of self-tolerance through the cross-reactive recognition of other alleles in DR4/DR"x" heterozygotes. Such an observation as this may contribute to our understanding of the etiopathology of rheumatoid arthritis, an autoimmune disease strongly associated with HLA-DRB1*0401.

Alleles↗
PubMed1997

Dissociation of T cell anergy from apoptosis by blockade of Fas/Apo-1 (CD95) signaling.

Induction of anergy and deletion due to apoptosis are two of the mechanisms involved in peripheral tolerance. To clarify the relationship between these two phenomena we have used an in vitro system of T cell Ag presentation. The recognition of Ag displayed by MHC class II-expressing T cells (T-APC) induces partial signals in Ag-specific T cell clones. This leads to a blunted intracellular calcium flux, and the T cells become unable to proliferate in response to further challenge with professional APC. These T cells are unable to produce IL-2, but retain the ability to release IL-4. In the present study, we report that for some T cell clones, the predominant outcome of Ag recognition on T cells is cell death. For susceptible T cell clones, the number of cells that die is proportional to the peptide concentration. This cell death resulted from Fas/Apo-1 (CD95)/Fas-ligand interactions between the T cells, in that Fas ligand expression was detected following overnight culture of T cells with T-APC and neutralizing anti-CD95 Ab protected from death. Most notably, following anti-CD95-mediated protection from apoptosis, the rescued T cells remained unable to respond to rechallenge with Ag-pulsed, professional APC. These data suggest that anergy and apoptosis can be separated as consequences of partial T cell signaling.

Antibodies, Blocking↗
PubMed1997

Anergic T cells effect linked suppression.

Although the phenomenon of T cell-mediated suppression is well established, particularly in experimental models of transplantation, the mechanisms involved in this form of immunoregulation remain controversial. We have recently demonstrated, using an in vitro system, that anergic T cells can act as suppressor cells by competing for the membrane of the antigen-presenting cell (APC) and for locally produced interleukin-2. In the experiments described here we have explored the ability of anergic T cells to effect linked suppression in antigen-specific and allospecific responses. We observed that anergic antigen-specific CD4+ T cells can inhibit T cells restricted by a different major histocompatibility complex (MHC) class II molecule provided that both restriction elements are expressed by the same APC. In addition, anergic allospecific clones could also effect linked suppression since they could regulate not only T cells specific for the same alloantigen but also responder T cells with direct allospecificity for a second allogeneic MHC molecule or with indirect, self MHC-restricted allospecificity for a processed MHC class I alloantigen. Furthermore, the regulatory effect of the anergic T cells was dependent on cell contact, was not dependent upon irradiation, and was maintained during in vitro culture. These data demonstrate that linked suppression can be effected by anergic T cells in vitro. In the clinical context this raises the possibility that induction of tolerance to a single alloantigen could serve to regulate the immune response to an allograft carrying several MHC and minor antigen differences.

Animals↗
PubMed1996

The TAP complex influences allorecognition of class II MHC molecules.

The influence of the TAP complex on T-cell allorecognition of MHC class II molecules was examined using human B-cell lines that have mutations in the TAP 1 or 2 genes. The TAP mutations led to the loss of allorecognition for two of 28 anti- HLA-DR T-cell clones. Restoration of TAP expression by transfection of a TAP 2 cDNA clone led to recovery of the alloresponse for both clones. These results could be explained in two ways. First, TAP dependence could reflect specificity for a peptide derived from an MHC class I molecule that is less efficiently generated by the endocytic pathway in the TAP-deficient stimulator cells owing to reduction in surface class I expression. The proliferative responses of these clones to the TAP-deficient stimulator cells was not restored by rescue of cell-surface expression of class I molecules by low temperature culture or by the addition of class I-binding peptides. These data therefore favor the alternative explanation that class II loading by some peptides is TAP dependent. Circumstances that lead to the amplification of this minority pathway of endogenous presentation by class II MHC molecules may have the potential to interrupt self-tolerance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Major histocompatibility complex class II-expressing endothelial cells induce allospecific nonresponsiveness in naive T cells.

The role of endothelial cells (EC) in initiating a primary T cell response is of importance in clinical transplantation and autoimmunity since EC are the first allogeneic target encountered by the recipient's immune system and may display tissue-specific autoantigens in the context of an inflammatory response. In this study, we have investigated the antigen-presenting cell function of human umbilical vein-derived EC (HUVEC), depleted of constitutively major histocompatibility complex class II+ cells and induced to express class II molecules by interferon-gamma. The results show that HUVEC do not express B7 but can support proliferation by antigen-specific T cell clones. In contrast, they were unable to initiate a primary alloresponse using three independent HUVEC cultures and MHC class II-mismatched CD4+ T cells from eight donors. The response to HUVEC was reconstituted by trans-costimulation provided by DAP.3 transfectants expressing human B7.1. Coculture of peripheral blood T cells with EC expressing allogeneic DR molecules had markedly different effects on CD45RO+ and RA+ subsets. Subsequent reactivity of the RO+ T cells was unaffected by exposure to EC, indicating a neutral encounter. In contrast, culture with DR+ EC induced allospecific nonresponsiveness in RA+ T cells.

Antigen Presentation↗
PubMed1993

Position 71 in the alpha helix of the DR beta domain is predicted to influence peptide binding and plays a central role in allorecognition.

Despite all the structural and functional data that have been accumulated regarding major histocompatibility complex (MHC) class II molecules during recent years, the relative contribution of putative T cell receptor (TcR)-contacting residues and peptide-binding MHC polymorphisms to MHC-restricted and allospecific T cell responses remains a point of contention. Some authors emphasize the importance of direct interaction between the allospecific TcR and polymorphic MHC residues whereas other emphasize the role of naturally processed MHC-bound peptides. We have previously described a new HLA-DRB1 allele: DR BON (DRB1*0103). This gene differs from DRB1*0101 by six base pairs clustered in the third variable region of the second exon leading to three amino acid changes at positions 67, 70 and 71 of the beta chain of the HLA-DR molecule. To define the respective role of these residues in allorecognition, we have performed site-directed mutagenesis on the DRB1*0103 allele to create six mutants which are intermediary between the DR BON and the DR1 alleles. These mutant cDNA were expressed in mouse fibroblasts and the transfectants with the highest expression of class II molecules were used as stimulators for a panel of ten anti-DR BON and five anti-DR1 alloreactive T cell clones. We demonstrate that the residue at the peptide-binding position 71 is of paramount importance in the alloresponse of these clones. In addition some clones were sensitive to amino acid substitution at the TcR-contacting position 70, while substitution at position 67 affects very few clones. The dominance of residue 71 was also observed with an influenza hemagglutinin-specific HLA-DR BON-restricted T cell line.

Amino Acid Sequence↗